This invention relates to a method of forming a bioabsorbable copolymer of specific and well defined molecular architecture, to the copolymer made by the method and to a medical or surgical device manufactured from the copolymer.
The following U.S. Pats. are considered to be background to the present invention: U.S. Pat. Nos. 3,023,192, 3,766,146, 3,268,487, 4,157,437, 4,157,921, 4,243,775, 4,246,904, 4,300,565, 4,429,080, 4,314,561, 4,605,730, 4,700,704, 4,643,191, 4,653,497, 4,716,203, and 4,838,267; and publication WO. 89/05664. These patents and the publication are incorporated herein by reference.
The term "molecular architecture," which is used in describing the present invention, refers to copolymers categorized as statistical (also called random), block or segmented (also called multi-block or random-block). Block copolymers can be diblocks, often symbolized as an AB block structure, or triblocks, often symbolized as an ABA block structure. Other block structures known in the art are "star-block" copolymers and "graft-block" copolymers. Segmented copolymers are sometimes symbolized as an (AB).sub.n block structure. All of these architectures are well known to those skilled in polymer science.
The use of segmented copolymers in the preparation of medical devices is well known in the prior art. Interest in these materials stems from their excellent mechanical properties, which include combinations of their elastomeric behavior, high tensile strength, low stress relaxation (creep) and resistance to long term flexural fatigue failure. The excellent mechanical properties of these copolymers can be attributed to phase separation (domain formation) of the often noncrystalline "soft" segments and often crystalline "hard" segments contained within the copolymer chain. The soft segment contributes to the elastomeric behavior of the copolymer while the hard segment non-convalently crosslinks the copolymer and adds mechanical strength and toughness.
A vast quantity of literature exists which describes the relationship of molecular architectural parameters to polymer physical properties for non-absorbable copolymers. Background information on this field can be found in Allport, D.C., et al., "Property Structure Relationships in Polyurethane Block Copolymers," in Block Copolymers, Allport, D.C., and James, W.H., eds., John Wiley & Sons, 1973, pp 443-492 and in Polymer Alloys: Blends, Blocks, Grafts and Interpenetrating Networks, Klemper, D. and Frisch, K.C., eds., Plenum Press, 1979 and in Polymer Alloys II: Blends, Blocks, Grafts and Interpenetrating Networks, Klemper, D. and Frisch, K.C., eds., Plenum Press, 1979. These publications are incorporated herein by reference. The prior art in the field of non-absorbable polymers teaches one skilled in the art of the importance of molecular architecture in determining material physical properties. Examples of non-absorbable copolymeric materials having a segmented molecular architecture that have been used in medical applications are HYTREL (a DuPont polyester), PELLETHANE (an Upjohn polyurethane) and BIOMER (an Ethicon polyurethane), which are incorporated herein by reference.
The use of cyclic ester monomers in the preparation of block copolymers is known in the art. Investigators have used low temperature polymerication methods, often in solution, and exotic catalysts to avoid transesterification reactions to obtain a variety of block copolyesters which may be absorbable. Reference is made to the following relevant literature articles: Toyssio, P,H,, et al., J. Polym. Sci., 15, 1035-1041 (1977), Pong, X,D,, et al., J. Polym. Sci., Polym. Lett., 21, 593-600 (1983), Inoue, S., et al., Macromolecules, 17, 2217-2222 (1984) and Song, C. X. and Pong, X. D., Macromolecules, 17, 2764-2767 (1984). These publications are incorporated herein by reference. Such "living polymerization" methods, due to the need for organic solvents, are not desirable for producing medical goods, and are not advantageous for commercial scale applications. Also, these methods are not easily adaptable to the preparation of copolymers with a broad range of segment lengths within a single polymerization.
The concept of sequential addition copolymerization for copolymers of glycolide and lactide was first disclosed by Klootwijk in U.S. Pat. No. (hereafter "U.S.") 3,268,487. Specific examples of glycolide/lactide sequential addition copolymers were taught by okuzumi, et al. in U.S. Pat. No. 4,157,437 and U.S. Pat. No. 4,157,921. Further examples of glycolide/lactide, .epsilon.-caprolactone/glycolide and trimethylene carbonate (with a variety of comonomers) are taught by Rosensaft, et al., in U.S. Pat. No. 4,243,775 and U.S. Pat. No. 4,300,565. Still further specific examples of trimethylene carbonate/glycolide copolymers suitable for use as sutures are taught by Casey and Roby in U.S. Pat. No. 4,429,080. Finally, copolymers of .epsilon.-caprolactone and glycolide (U.S. Pat. No. 4,605,730 and U.S. Pat. No. 4,700,704); p-dioxanone and lactide (U.S. Pat. No. 4,643,191), p-dioxanone and glycolide (U.S. Pat. No. 4,653,497 and U.S. Pat. No. 4,838,267), .epsilon.-caprolactone and other monomers (U.S. Pat. No. 4,788,979), and lactide and trimethylene carbonate (WO 89/05664) have been synthesized. The U.S. Pat. No. 4,788,979 is incorporated herein by reference.
While these patents teach the preparation of block copolymers via a sequential route, the concept of preparing segmented copolymers from cyclic esters with control over both the average segment length and the distribution of segment lengths has not yet been addressed in the prior art. It is the object of this invention to prepare block and segmented copolymers with predictable molecular architectures having good control over the segment lengths and segment length distributions.
Such a copolymerization method results in copolymers with unexpected architectures. For example, since transesterification is known to occur in all esters, it is unexpected to prepare well defined block copolymers, that is block copolymers without the complication of transesterification reactions, of the A-B or (A-B).sub.n type under commonly used melt copolymerization conditions. However, we have found that when cyclic ester monomers such as .epsilon.-caprolactone or trimethylene carbonate are employed in the first stage of the polymerization, well defined block copolymers are formed without the complications of reshuffling or scrambling reactions. It is to be understood that in this application the term "epsilon-caprolactone" will be described by using both the Greek letter for epsilon and the arabic letter "e". That is, in this application the terms "epsilon-caprolactone", ".epsilon.-caprolactone", and "e-caprolactone" are synonomous.
A second example of an unexpected result, is that addition of a minor amount of a second monomer (such as glycolide or lactide) to the .epsilon.-caprolactone or trimethylene carbonate in the first stage of the copolymerization followed by the addition of a 2nd stage comprised largely of the second comonomer, results in copolymers with segmented, or (A-B).sub.n, architectures with controllable and well-defined segment lengths. Such copolymers display markedly different physical properties as compared to corresponding random or block copolymers of similar composition.
Still further, by varying the polymerization time following the second stage addition, to times beyond full conversion of monomer to polymer, one can control the distribution of segment lengths. This occurs with no change in overall conversion or copolymer composition. Segment length distribution has also been found to have a marked effect on the physical and mechanical properties of the resulting copolymers. For a given composition as the segment length distribution narrows with polymerization time, properties such as melting point, and degree of crystallinity decline, and their related physical and mechanical properties change accordingly.
Still further, it is unexpected that increasing the concentration of monomer known to form "hard segments" results in copolymers with lower melting point and degree of crystallinity and greater flexibility. However, we have found that in the segmented copolymers of this invention, such an effect has been observed.
These materials may find use as absorbable medical or surgical devices where control over mechanical properties such as strength, stiffness and toughness is needed. Specific utility as a medical or surgical device includes, but is not limited to, a surgical suture and a controlled release device. Another utility of the copolymer of this invention may be as a surgical mesh or a tubular article, for example a vascular graft.